Tumor necrosis factor receptor modulator spermatogenesis‐associated protein 2 is a novel predictor of outcome in ovarian cancer

Abstract

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor‐α ( TNF ‐α) as a key mediator. Recently, spermatogenesis‐associated protein 2 ( SPATA 2) was identified as a TNF receptor modulator which is required for TNF ‐induced inflammation and apoptosis. The available data on TNF ‐α in ovarian cancer ( OC ) are inconsistent, and SPATA 2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA 2 and TNFA by quantitative real‐time polymerase chain reaction in tissues of 171 patients with low‐grade serous ( LGSOC ), high‐grade serous ( HGSOC ), endometrioid and clear cell OC compared with 28 non‐malignant control tissues. We stimulated OC cells ( OVCAR 3) with pro‐inflammatory ( TNF ‐α, interleukin [ IL ]‐1β) and mitogenic stimuli ( IL ‐6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA 2 . Pro‐inflammatory, but not mitogenic stimuli, potently induced SPATA 2 expression in OC cells. Expression of TNFA and SPATA 2 was higher in OC compared with control tissues ( P = 0.010 and P = 0.001, respectively) and correlated with each other ( P = 0.034, r s = 0.198). When compared with grade 1 cancers, SPATA 2 was expressed higher in grade 2 and 3 tumors ( P = 0.011) as well as in HGSOC compared with LGSOC ( P = 0.024). Multivariate survival analyses revealed that OC with high SPATA 2 expression were associated with reduced progression‐free survival ( P = 0.048) and overall survival ( P < 0.001). In conclusion, SPATA 2 expression is regulated by TNF ‐α and IL ‐1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA 2 in tumorigenesis which warrants further investigation in gynecological malignancies.